1. Field of the Invention
The present invention relates to a novel method of administering narcotic antagonists, narcotic analgesics and related compounds, and to novel dosage forms containing such compounds adapted for nasal administration.
2. Background Art
Morphine, which has the structural formula ##STR1## is a potent narcotic analgesic which is principally used to relieve pain; it is also used in the dyspnea of heart failure, in pulmonary edema and cough, as a sedative and in the control of diarrhea (chiefly in the form of paragoric). Morphine causes both depression and stimulation in the central nervous system and the gut, its most significant actions being analgesia, hypnosis, respiratory depression, smooth muscle spasm, nausea, vomiting and circulatory and other effects (especially miosis). The drug is well-absorbed by injection, but absorption via the oral route is inefficient and variable, probably because of metabolism in the liver, chiefly by conjugation with glucuronic acid. Abuse leads to habituation or addiction.
The morphine molecule has been subjected to a variety of structural modifications in efforts to enhance selected properties and/or to deemphasize others, as well as to produce drugs which actually antagonize the effects of morphine and other opioid analgesics. Such efforts have led to the development of a variety of classes of chemical compounds, such as the class of morphine analogues whose structures are very closely allied to that of morphine, retaining both the phenolic OH and the N-methyl substituent of morphine, such as apomorphine, levorphanol and oxymorphone, and which as a group have strong analgesic, respiratory depressant and smooth muscle stimulant activity but which also are highly addicting. Retention of the phenolic hydroxyl while replacing the methyl on the nitrogen atom with a larger alkyl or similar side-chain has afforded both morphine analogues which are relatively pure opioid antagonists (e.g. naloxone and naltrexone) and are used in the treatment of narcotic-induced respiratory depression (overdose), in the diagnosis of narcotic addiction and in the prophylaxis of narcotic abuse; and morphine analogues which are agonist-antagonists (e.g. buprenorphine, pentazocine, nalorphine and cyclazocine), which display varying degrees of morphine-like activity as well as of morphine-antagonist behavior, and which can therefore be used as analgesics as well as for the purposes for which the relatively pure antagonists are used. Buprenorphine appears to be a particularly valuable analogue because of its low physical dependence potential, as well as its potent narcotic antagonist and analgesic activity. See Cowan et al, Br. J. Pharmac. (1977), 60, 537-545; Jasinski et al, Arch. Gen. Psychiatry, Vol. 35, April 1978, 501-516; Mello et al, Science, Vol. 207, Feb. 8, 1980, 657-659.
Virtually all of the members of the groups of morphine analogues discussed supra are well-absorbed by injection, but are rarely used orally because of inefficient and variable absorption by that route. The low effectiveness of naloxone when taken orally has been attributed to the rapid and almost total formation of a less active metabolite in the first hepatic transit. See Fishman et al, J. Pharmacol. Exp. Ther. 187, 575-580 (1973). Also Berkowitz et al, J. Pharmacol. Exp. Ther. 195, 499-504, and the references cited therein.
Yet other structural modifications of the morphine molecule have resulted in codeine and its analogues; methadone and related compounds; and meperidine and related compounds such as profadol. Also see, generally, Pharmacological Basis of Therapeutics, ed. Goodman and Gilman, sixth edition, Chapter 22, "Opioid Analgesics and Antagonists", by Jaffe and Martin, pp. 494-534 (MACMILLAN PUBLISHING CO., INC., New York, 1980); Cutting's Handbook of Pharmacology, sixth edition, ed. T. Z. Czaky, M.D., Appleton-Century-Crofts/New York, Chapter 50, pp. 551-571.
Recent studies of THC, or .DELTA..sup.9 -tetrahydrocannabinol, which is the active ingredient in marijuana, or its derivatives (e.g. CBD or cannabidiol, and levonantradol) suggest that these compounds are potentially useful in a wide variety of therapeutic areas, such as in the prevention of narcotic withdrawal symptoms and as antiemetics, particularly in the treatment of cancer patients undergoing chemotherapy. Unfortunately, oral administration has been found to be much less effective than intramuscular injection. See, Medical News, Monday, Jan. 19, 1981, page 3, for a more detailed discussion of the various therapeutic uses of THC and its derivatives.